P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice

Wang, Jing; Gan, Changpei; Sparidans, Rolf W.; Wagenaar, Els; Hoppe, Stéphanie van; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1016/j.phrs.2017.11.006

Cited by 37 publications

(30 citation statements)

References 36 publications

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“…In this work, we have shown that ABCG2 plays an important role in the passage of meloxicam through BBB and its accumulation in the central nervous system. Several studies have demonstrated the limiting role of ABCG2 in the brain penetration of many drugs [49,50] and how transporter inhibition [51,52] or reduced expression due to genetic variants [24] can improve drug therapies related to the central nervous system. We therefore hypothesized that inhibition of ABCG2 could increase brain accumulation of meloxicam, and consequently, improve the potential treatment or prevention of neurodegenerative diseases with this drug.…”

Section: Discussionmentioning

confidence: 99%

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

García-Lino

Blanco-Paniagua

Astorga-Simon

et al. 2020

Biochemical Pharmacology

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ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg•h/ml versus 73.80 ± 10.00 µg•h/ml). Differences in meloxicam distribution were reported for several tissues, with a 20-fold higher concentration in the brain of Abcg2-/compared to wild-type mice. Meloxicam secretion into milk was also affected by the transporter, with a 2.5-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/lactating female mice (0.58 ± 0.08 versus 0.23 ± 0.06). We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.

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Section: Discussionmentioning

confidence: 99%

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

García-Lino

Blanco-Paniagua

Astorga-Simon

et al. 2020

Biochemical Pharmacology

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“…A key mechanism responsible for restricting drug delivery to the brain is active efflux at the BBB, often mediated by P-glycoprotein [(P-gp), Abcb1/P-gp] and breast cancer resistance protein [(Bcrp), Abcg2/Bcrp] (Gampa et al, 2016(Gampa et al, , 2017Kim et al, 2018). Previous studies have indicated that vemurafenib, dabrafenib, encorafenib, trametinib, cobimetinib, and binimetinib will have limited brain distribution due to efflux by P-gp and/or Bcrp (Mittapalli et al, 2012(Mittapalli et al, , 2013Choo et al, 2014;Vaidhyanathan et al, 2014;de Gooijer et al, 2018;Wang et al, 2018). The drug delivery to brain tumors with heterogeneous disruption of the BBB can be highly variable for compounds that show a limited BBB penetration.…”

Section: Introductionmentioning

confidence: 99%

Brain Distribution and Active Efflux of Three panRAF Inhibitors: Considerations in the Treatment of Melanoma Brain Metastases

Gampa

Kim

Mohammad

et al. 2019

J Pharmacol Exp Ther

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Targeted inhibition of RAF and MEK by molecularly targeted agents has been employed as a strategy to block aberrant mitogen-activated protein kinase (MAPK) signaling in melanoma. While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAFmutant melanoma, initial responses are often followed by relapse due to acquired resistance. Moreover, some BRAF inhibitors are associated with paradoxical activation of the MAPK pathway, causing the development of secondary malignancies. The use of panRAF inhibitors, i.e., those that target all isoforms of RAF, may overcome paradoxical activation and resistance. The purpose of this study was to perform a quantitative assessment and evaluation of the influence of efflux mechanisms at the blood-brain barrier (BBB), in particular, Abcb1/P-glycoprotein (P-gp) and Abcg2/breast cancer resistance protein (Bcrp), on the brain distribution of three panRAF inhibitors: CCT196969 [1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy) phenyl)urea], LY3009120 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido(2,3-d)pyrimidin-6-yl)phenyl)urea, and MLN2480 [4-pyrimidinecarboxamide, 6-amino-5-chloro-N-[(1R)-1-[5-[[[5-chloro-4-(trifluoromethyl)-2pyridinyl]amino]carbonyl]-2-thiazolyl]ethyl]-]. In vitro studies using transfected Madin-Darby canine kidney II cells indicate that only LY3009120 and MLN2480 are substrates of Bcrp, and none of the three inhibitors are substrates of P-gp. The three panRAF inhibitors show high nonspecific binding in brain and plasma. In vivo studies in mice show that the brain distribution of CCT196969, LY3009120, and MLN2480 is limited, and is enhanced in transgenic mice lacking P-gp and Bcrp. While MLN2480 has a higher brain distribution, LY3009120 exhibits superior in vitro efficacy in patient-derived melanoma cell lines. The delivery of a drug to the site of action residing behind a functionally intact BBB, along with drug potency against the target, collectively play a critical role in determining in vivo efficacy outcomes.

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“… 41 These enzymes can also function as drug resistance regulators that induce drug resistance or losses in drug efficiency by metabolizing and detoxifying chemotherapeutics during treatment. 42 – 46 To further establish the role of PXR in sorafenib resistance, the current study revealed that LINE-1 ORF-1p could interact with PXR and function as a PXR coregulator.…”

Section: Discussionmentioning

confidence: 92%

LINE-1 ORF-1p enhances the transcription factor activity of pregnenolone X receptor and promotes sorafenib resistance in hepatocellular carcinoma cells

Chang

Zeng

Liu

et al. 2018

CMAR

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BackgroundLINE-1 ORF-1p is encoded by the human pro-oncogene LINE-1. Our previous work showed that LINE-1 ORF-1p could enhance the resistance of hepatocellular carcinoma (HCC) cells to antitumor agents. However, the mechanisms involved in LINE-1 ORF-1p-mediated drug resistance remain largely unknown.Materials and methodsThe endogenous mRNA level of LINE-1 ORF-1p in clinical HCC specimens was examined using quantitative PCR (qPCR). The prognosis of HCC patients was assessed using time to progression and overall survival. The transcription factor activity of pregnenolone X receptor (PXR) was examined using luciferase gene reporter assays, qPCR, chromatin immunoprecipitation assays and cellular subfraction assays. Protein interaction between LINE-1 ORF-1p and PXR was detected by co-immunoprecipitation. The effect of LINE-1 ORF-1p on sorafenib resistance in HCC cells was studied using in vitro and in vivo models.ResultsA high level of LINE-1 ORF-1p in clinical specimens was related to poor prognosis in patients who received sorafenib treatment. LINE-1 ORF-1p increased the transcription factor activity of PXR by interacting with PXR and enhancing its cytoplasmic/nuclear translocation, and recruiting PXR to its downstream gene promoter, in turn enhancing the expression of the sorafenib resistance-related genes, CYP3A4 and mdr-1. LINE-1 ORF-1p enhanced the resistance to and clearance of sorafenib in HCC cells.ConclusionLINE-1 ORF-1p enhances the transcription factor activation of PXR and promotes the clearance of and resistance to sorafenib in HCC cells.

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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) affect brain accumulation and intestinal disposition of encorafenib in mice

Cited by 37 publications

References 36 publications

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

Brain Distribution and Active Efflux of Three panRAF Inhibitors: Considerations in the Treatment of Melanoma Brain Metastases

LINE-1 ORF-1p enhances the transcription factor activity of pregnenolone X receptor and promotes sorafenib resistance in hepatocellular carcinoma cells

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